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Tyrosine Kinase Inhibitory
June-Won CheongYonsei University College of MedicineYonsei University College of Medicine
Part IPart I
Protein KinasesProtein Kinases
Cellular communicationCellular communication• Signal transduction pathways• Signal transduction pathways• 3 stages of cell signalling
receptionreceptiontransductionresponseresponse
G-protein-linked
ProteinKinase
receptor receptor
Protein KinasesProtein KinasesTyrosine Kinases Serine/threonine Kinases
ABL Abelson PKC Protein kinase C
y
KITR c-Kit receptor CDK Cyclin-dep. kinase
PDGFR PLT-derived-GF receptor MKK1 Mitogen-act. PK kinase 1
EGFR Epidermal-GF receptor RAF Rapidly accelerated fibrosarcoma
ERB2R Erb2 receptor CHK1 Checkpoint kinase 1
VEGFR Vascular-endothelial GF receptor mTor Mammalian Target of rapamycin
FGFR Fibroblast-GF receptor ROCK RHO-dep. PK
NGFR Nerve-GF receptor p38/SAPK2a P38/Stress-act. PK2a
MLK Mixed-lineage PK
Protein Kinases as a TargetProtein Kinases as a Target• 200 300 PKs in a cell• 200-300 PKs in a cell • Upstream/downstream of relevant oncogenes ortumor suppressor genes
• Commonality & diversity among ATP-binding sitesCommonality & diversity among ATP binding sites of PKsP ibilit f t i t lid ti• Possibility of a step-wise concept validationat the biochemical, cellular & intact animal level ,as proof of concept in the clinic
Protein Kinases & CancerProtein Kinases & CancerOverexpression of GFRs
EGFR HER2 HER3 HER4 i b t l H&N d li bl t•EGFR,HER2,HER3,HER4 in breast, ovary, lung, H&N and glioblastoma•FGFR in lung, ovary and breast•PDGFR in glioblastoma•IGF-1R in solid tumors
Overexpression of GFs•TGF-α in carcinoma overexpressing the EGFR•PDGF-BB expression in glioblastoma•VEGF expression for neo-vascularization (angiogenesis and metastasis)p ( g g )
Altered PK levels and/or activities•Bcr-Abl in CML (95%), ALL (15%)•c-Met in renal carcinoma•c-Kit in gastric cancers (GIST)•Cancers with Onc Ras have deregulated PKC, Raf-kinase (bladder, colon, lung, breast)Cancers with Onc Ras have deregulated PKC, Raf kinase (bladder, colon, lung, breast)•Deregulation of cell cycle by CdKs
Protein KinaseProtein Kinase
Protein Kinase Inhibitor; PKIProtein Kinase Inhibitor; PKIIsoquinoline sulfonamides•From 1st PKI (Naphthalene sulfonamide)From 1 PKI (Naphthalene sulfonamide)
•cAMP- & cGMP-dept. PKI
Hidaka H et al. Biochemistry 1984;23:5036
Protein Kinase Inhibitor; PKIProtein Kinase Inhibitor; PKIStaurosporine•Antifungal agent (1977)•Antifungal agent (1977)
•From Streptomyces
•Indolocarbazole product
•Nanomolar inhibitor of PKC
K252 CEP-1347K252, CEP-1347,
UCN-01, PKC412, etc…Tamaoki T et al. Biochem Biophys Res Commun 1986;135:397
Kase H et al. J Antibiot 1986;39:1059
Protein Kinase Inhibitor; PKIProtein Kinase Inhibitor; PKI
Knighton DR et al. Science 1991;253:407/414
Part IIPart II
Tyrosine Kinases & TKITyrosine Kinases & TKI
Tyrosine KinasesTyrosine Kinases
www.uic.edu/.../mike/spring2003/lect07.htm
https://eapbiofield.wikispaces.com/file/view/11_07cRecTyrosineKinases-L.jpg
Important discoveries in TKImportant discoveries in TK
Hunter T. Curr Opin Cell Biol 2009;21:140
TKI discoveryTKI discoveryTarget TK Inhibitor Company
*Bcr-Abl, c-Kit, PDGFR STI 571 (Imatinib, GLIVEC) Novartis* CSF 1R EPHA4R AMN107 (Nil ti ib TASIGNA) N ti*, CSF-1R, EPHA4R AMN107 (Nilotinib, TASIGNA) Novartis
*, SRC, EPHR BMS 354825 (Dasatinib, SPRYCEL) BMS*, SRC SKI 606 (Bosutinib) Wyeth-AyerstEGFR ZD1839 (Gefitinib, IRRESA) AstraZenecaEGFR OSI 774(Erlotinib,TARCEVA) OSI Pharmaceuticals
EGFR, ERB2R PKI 166 NovartisEGFR, ERB2R CI 1033 (Canertinib) PfizerEGFR, ERB2R EKB 569 Wyeth-AyerstEGFR, ERB2R GW 572016 (Lapatinib, TYKERB) GlaxoSmithKline, ( p , )
VEGFR PTK 787 NovartisVEGFR ZK 222584 Schering-PloughVEGFR SU 5416 (TSU-16) Sugen/Pharmacia UpjohnVEGFR SU 5416 (TSU 16) Sugen/Pharmacia Upjohn
VEGFR, EGFR ZD 6474 (Vandetanib, ZACTIMA) AstraZenecaVEGFR, FGFR, PDGFR SU 11248(Sorafenib, SUTENT) PfizerVEGFR FGFR PDGFR SU 6668 (TSU 68) Pharmacia CorpVEGFR, FGFR, PDGFR SU 6668 (TSU-68) Pharmacia Corp.
bFGFR PD 173074 PfizerNGFR CEP 2583 Cephalon
Tyrosine Kinase Inhibitor; TKITyrosine Kinase Inhibitor; TKIInvestigation of catalytic mechanism of EGFRInvestigation of catalytic mechanism of EGFR•Structure-based searching & discovery of a potent inhibitorC t lli ti•Crystallization process
Ward WH et al. Biochem Pharmacol 1994;48:659
PD153035PD153035•EGFR inhibitor
Fry DW et al. Science 1994;265:1093
AG1478•EGF-dept. activation of Src-family TK inhibitor
Osherov N et al. Eur J Biochem 1994;225:1047
Tyrosine Kinase Inhibitor; TKITyrosine Kinase Inhibitor; TKI4-(Phenylamino)pyrrolopyrimidines4-(Phenylamino)pyrrolopyrimidines •By pharmacophore model of ATP binding siteEGFR TKI•EGFR TKI Traxler P et al. J Med Chem 1996;39:2285
PKI166 66•By optiminization process•EGFR/erbB-2 TKIEGFR/erbB 2 TKITraxler P et al. Clin Cancer Res 1999;5:3750s
Tyrosine Kinase Inhibitor; TKITyrosine Kinase Inhibitor; TKI
Folia Pharmacol Jpn. 2003;122:482
Part IIIPart III
Individual TKIsIndividual TKIs
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study
ImatinibRA
y
Crossover
ANDO
n = 553
IFN-α+
OMIZ +
Ara-C Crossover for:• Lack of response
ZE
553 p• Loss of response• Intolerance of treatment• Reluctance to continue IFN
n = 553
• Reluctance to continue IFN
O’Brien SG et al. N Engl J Med 2003;348:994
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS studyy
O’Brien SG et al. N Engl J Med 2003;348:994
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS studyy
MCyR PFS
O’Brien SG et al. N Engl J Med 2003;348:994
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study – 7 yrs after
All randomized to imatinib(n= 553; 100%)
y y
(n 553; 100%)
Still receiving study imatinib(n = 332; 60%)
Discontinued study imatinib*(n = 221; 40%)( ; )
In CCR (n = 317;
No CCR (n = 15;
(n 221; 40%)
(n 317; 57%)
(n 15; 3%) Safety
(n = 43; 8%)
Efficacy (n = 82;
15%)
Other (n = 96;
17%)
Alive Dead Alive Dead Alive Dead(n = 17;
40%)(n = 26;
60%)(n = 52;
63%)(n = 30;
37%)(n = 81;
84%)(n = 15;
16%)
O’Brien SG et al. Blood 2008;112: Abstract 186.
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study – 7 yrs aftery y
90
100
t
80
90
Estimated OS at 7 years is 86% (94% considering only CML-related deaths)ut
Eve
nt
60
70
( g y )
% W
itho
40
50
Survival: deaths associated with CMLOverall Survival
%
20
30
Overall Survival
0
10
0 1 2 3 4 5 6 7 8 year after random.
O’Brien SG et al. Blood 2008;112: Abstract 186.
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study – 7 yrs after
90
100
s
y y
BCR-ABL% (IS)
≤0.1%≤0.01%
70
80
90
e Sa
mpl
es
≤0.01%
50
60
Avai
labl
e
20
30
40
% o
f A
0
10
20
Sample Analysis Time Points (months)0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84
Hughes et al. Blood 2008;112: Abstract 334.
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
Time Failure Suboptimal Response Warnings
Dx
•High risk •Del9q+ •Additional ch’somal abNLs in Ph+ cellsPh cells
3 m No HR < CHR
6 m No CHR or CyR < PCyR
12 m < PCyR PCyR < < CCyR Any MR < MMRy y y y
18 m < CCyR < MMR
Any•Loss of CHR •Loss of CCyR
•Additional ch’somal abNLs in Ph+ cells •Increase in BCR-Any
time•Loss of CCyR •Mutation with high insensitivity to Glivec
abNLs in Ph+ cells •Loss of MMR •Mutation with low insensitivity to Glivec
ABL level •Other ch’somal abNLs in Ph-cells
Baccarani M et al. Blood 2006;108:1809.
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
(n=81)s 8090
100
( )
(n=19)6 m
onth
s
607080
Suboptimal
(n=16)
CC
yR >
6
304050
Failure
(n=16)
% C
102030 Failure
0
Months since randomization0 3 6 9 12 15 18 21 24 27 30 33
Druker et al. Blood 2003; 102: Abstract 634
CyR at 6 months (Ph+) 1-35% 36-65%66-95% >95%
Months since randomization
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
86%95%
P = 0.0190100
86%
62%vent 70
80
62%58%
thou
t Ev
5060
BCR ABL % (IS) at 18 months
% W
it
203040
≤0.1% (n = 164)>0.1-1% (n = 47)
BCR-ABL % (IS) at 18 months
01020
( )>1-10% (n = 25)>10% (n = 13)
Hughes et al. Blood 2008;112: Abstract 334.
00 12 24 36 48 60 72 84
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
Standard Frontline Tx for CML ; AP and BC patients
Overall CyR 48% Overall CyR 17%
PFS
Palandri F et al. Haematologica 2009;94:205 Palandri F et al. Haematologica 2008;93:1792
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
Standard Frontline Tx for CML ; AP and BC patients
Standard Frontline Tx for CML ; Bcr/Abl mutations20%
Data from the GIMEMA CML WP on 655 imatinib-resistant patients15%
10%
Data from the GIMEMA CML WP on 655 imatinib-resistant patients
5%
P-loop Catalytic domain
Activation loop
M351T L387M/F
H396R/PL248V
M343TV289A
D276GT277A
E281A/K L364I
oop domain loop
G250E
Q252R/HY253F/H
E255K/VT315I
F317L
E355G/DF359V/I
V379I
F311L/I
F382L S417Y/F
E459K/QF486S
T277A
A380T
E279KE292V
L384M
E453G/K
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
Standard Frontline Tx for CML ; AP and BC patients
Standard Frontline Tx for CML ; Bcr/Abl mutations....
2nd generation TKIsNilotinibNilotinib
Dasatinib
Bosutinib
Imatinib
Nilotinib Dasatinib BosutinibNilotinib Dasatinib Bosutinib
Potency & Selectivity of TKIsPotency & Selectivity of TKIs
Imatinib: PDGFR > Kit > BcrAbl > Src(Phos IC ) 72 nM 99 nM 192 nM >1000 nM(Phos IC50) 72 nM 99 nM 192 nM >1000 nM
Dasatinib: Src > BcrAbl > PDGFR > KitDasatinib: Src > BcrAbl > PDGFR > Kit(Phos IC50) 0.1 nM 1.8 nM 2.9 nM 18 nM
Nilotinib: BcrAbl > PDGFR > Kit > Src(Phos IC ) 19 nM 75 nM 209 nM >1000 nM(Phos IC50) 19 nM 75 nM 209 nM >1000 nM
Mestan J et al. Blood. 2004;104: Abstract 1978. Weisberg E et al. Cancer Cell 2005;7:129.
Nilotinib as a Second Tx for CP pts
100
Nilotinib, as a Second Tx for CP pts
95%
78%80
90
100
44%
56%59%65%
51%50
60
70
% 41%44%
30
40
50
Pat
ient
s, %
32120 321 226 2260
10
20
MCyR CCyRCHR
95321207 321 226 22695nOverall No BL
CHROverall Imatinib-
ResistantImatinib-Intolerant
Overall Imatinib-Resistant
Imatinib-Intolerant
321
y
Kantarjian HM, et al. J Clin Oncol. 2009;27(15S): Abstract 7029.
Patients with a minimum follow-up of 24 months
Nilotinib as a Second Tx for CP ptsNilotinib, as a Second Tx for CP pts
PFS
90
10089% 84% 78%
70
80
90
Dea
th
40
50
60
gres
sion
or D
20
30
40
With
out P
rog
Number of patients = 189Number failed = 35
0
10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
% W Number failed = 35
= Censored observations
Months Since MCyR
Kantarjian HM, et al. Blood. 2008;112: Abstract 3238.
Nilotinib as a Second Tx for CP pts
95%
Nilotinib, as a Second Tx for CP pts
OS
90
100
95% 87%
Aliv
e
60
70
80
% A
30
40
50
Number of patients = 321Number failed = 44
= censored observations10
20
30
00
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Months Since Start of Treatment
36
Kantarjian HM, et al. J Clin Oncol. 2009;27(15S): Abstract 7029.
• 87% of patients were estimated to be alive on nilotinib at 24 months
Dasatinib as a Second Tx for CP ptsDasatinib, as a Second Tx for CP ptsFor imatinib-resistant or –intolerant CML-CP pts.Prior imatinib 400 600 mg (48%) ≥600 mg (52%)Prior imatinib 400-600 mg (48%), ≥600 mg (52%)
Non-Hema SE(G3,4): ≤3% MCyRNon Hema SE(G3,4): 3%Hema SE(G3,4): 22-49%
MCyR
PFS
Hochhaus A et al. Blood 2007;109:2303
Dasatinib as a Second Tx for CP ptsDasatinib, as a Second Tx for CP pts
100 CHR100
80
9288 87
92 MCyRCCyR
80
60
63 61 63 61
5054
50 50
%
60
40
50 50 50
20
100 mg O D il
70 mg BID
140 mg O D il
50 mgBID
0Once Daily BID Once Daily BID
Shah NP, et al. Blood. 2008;112: Abstract 3225.
Dasatinib as a Second Tx for CP ptsDasatinib, as a Second Tx for CP pts
100
80R
88%
80
60s of
MC
yR
24-month response rates
CCyRMCyR
60
40
hout
Los
s
53%
CCyR
62%
MCyR20%
With
00 3 6 9 12 15 18 21 24 27 30
369 of 387 patients evaluable for molecular response
Shah NP, et al. Blood. 2008;112: Abstract 3225.
Months since MCyR
Dasatinib as a Second Tx for CP pts
94%97%
Dasatinib, as a Second Tx for CP pts
OS100
80
94%97%
91%
OS
80
60
80%91%
PFS60
40
%
20
00 3 6 9 12 15 18 21 24 27 30 33
Months
Shah NP, et al. Blood. 2008;112: Abstract 3225.
Nilotinib/Dasatinib AEsNilotinib/Dasatinib, AEs
Dasatinib Nilotinib
Dasatinib 70 mg BID, Nilotinib 400 mg BID
Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
Myelotoxicity - 49-50 - 28-30
(Thrombocytopenia & Neutropenia)49 50 28 30
Pleural Effusion (Peripheral Edema) 26 (29) 9 (1) 1 (6) 1 (0)
Bleeding 16 4 6 2
Hyperglycemia - - - 13
Lipase elevation - - - 15
Stone RM, et al. Blood. 2007;110: Abstract 734 / Kantarjian HM, et al. Blood. 2007;110: Abstract 735.
Nilotinib/Dasatinib as a Second Tx for CP2 yr % Nilotinib Dasatinib
Nilotinib/Dasatinib, as a Second Tx for CP2 yr % Nilotinib DasatinibCHR 95 92
MCyR 59 63CCyR 44 54
D MCyR 78 88D.MCyR 78 88PFS 80PFS 80OS 87 94
Nilotinib/Dasatinib AP2 yr % Nilotinib Dasatinib
Nilotinib/Dasatinib, as a Second Tx for AP2 yr % Nilotinib DasatinibCHR 31 53
MCyR 32 43CCyR 21 35
D MC R 66 75D.MCyR 66 (after MCyR) 75 (after MCyR)
PFS 55PFS 55OS 66
le Coutre PD, et al. J Clin Oncol. 2009;27(15S): Abstract 7057 / Kantarjian HM, et al. Blood. 15 April 2009. Epub ahead of print.
Dasatinib as a Second Tx for BC ptsDasatinib, as a Second Tx for BC pts116 imatinib-resistant or –intolerant CML-BC pts.Non Hema SE(G3 4): 0 24%Non-Hema SE(G3,4): 0-24%Hema SE(G3,4): 12-14%
MHR
PFS
Cortes J et al. Blood 2007;109:3207
Dasatinib for nilotinib-resistant PtsDasatinib for nilotinib-resistant PtsFor imatinib & nilotinib-resistant Ph(+) leukemiaN= 13 (CP 1 AP 9 BC 3)N= 13 (CP 1, AP 9, BC 3)Bcr-Abl mutation 100%140 mg/d (twice daily)140 mg/d (twice daily)Median Tx duration: 4 months (1-10)
OR: 57%CHR: 43%CHR: 43%CyR: 30%
Quintas-Cardama A et al. Blood 2006;109:497
Nilotinib for Dasatinib-resistant PtsNilotinib for Dasatinib-resistant Pts100
80
79%90
60
70
40
50 43%
20
3024%
0
10
20
Giles F et al. Blood 2008;112:1110
0CHR MCyR CCyR
Mutations recovered after TKI therapypy
*20ImatinibDasatinibNilotinib*
*
10
15
%
Nilotinib
* **
5
10
* *
0
5
* * * *
* T315I & F359V recovered after treatment with bosutinib
0G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R
BCR/ABL Mutation
T315I & F359V recovered after treatment with bosutinib
Jabbour E, et al. Blood. 2006;108: Abstract 750.
2nd generation TKIs2 generation TKIsRandomized Trials for Frontline TxRandomized Trials for Frontline Tx
Study Imatinib 2nd TKI No. of Pts Year started
USA-SWOG 400/800 Dasatinib 518 2005
Novartis 400 Nilotinib 845 2005
Wyeth 400 Bosutinib 2007
Nilotinib as a frontline TxNilotinib, as a frontline Tx
50% 80% 90% 83% 98% 97% CCyR
90%100%
y
< CCyR
60%70%80%
40%50%60%
10%20%30%
High Risk (n=10)Months
Non-High Risk (n=63)
0%3 6 12 3 6 12
High Risk (n=10) Non High Risk (n=63)
Rosti G, et al, Presented at: 14th Congress of the EHA; 2009: Berlin, Germany. Abstract 1090.
Nilotinib as a frontline Tx
3% 21% 52% 66% 73% 85%
Nilotinib, as a frontline Tx
100%MMR
80%
90%100% < MMR
NE
60%70%
80%
40%
50%
10%
20%
30%
Months0%
10%
1 2 3 6 9 12
Rosti G, et al, Presented at: 14th Congress of the EHA; 2009: Berlin, Germany. Abstract 1090.
Dasatinib as a frontline Tx
N 48 N 43 N 37 N 32 N 25 N 15
Dasatinib, as a frontline Tx
N = 48 N = 43 N = 37 N = 32 N = 25 N = 15
34
65
1790
100
nse CCyR
PC R417
70
80
Res
pon PCyR
93848895937940
50
60
ge w
ith
20
30
40
erce
nta
0
10
20
3 6 12 18 24 30
Pe
Cortes J, et al. Blood. 2008;112: Abstract 446.
3 6 12 18 24 30Months on Therapy
Dasatinib as a frontline Tx
100
Dasatinib, as a frontline Tx
80
100% MMR % CMR
60 644
60
espo
nse
41
7
82
40
e w
ith R
e
20 24 27
2
220
erce
ntag
MonthsN 46 45 42 37 31 25 14
20
3 6 9 12 18 24 30
Pe
Cortes et al. Blood 2008;112: Abstract 182.
Nilotinib/Dasatinib as a Frontline Tx for CP1 yr % Nilotinib Dasatinib
Nilotinib/Dasatinib, as a Frontline Tx for CP1 yr % Nilotinib DasatinibCCyR* 96 95y≥MMR 85 95
* Imatinib: 74%
• 2nd generation TKIs can improve outcome of pts with early CP-CML
• Responses with nilotinib/dasatinib are better & faster than imatinib
• Nilotinib is better tolerated and more selective than dasatinib
More approved TKIsMore approved TKIs….ATP-Binding
T315I-Active Nonkinase InhibitionBcr-Abl Abl & Src
Imatinib Dasatinib MK-0457 17-AAG
Nilotinib Bosutinib KW-2449 HDAC
INNO-406 XL228 DAC
AT9283 HHT
PHA-739358
CASE 168/F, CML-CP in Jan 2004.Frontline Tx: Imatinib 400 mg/d. At 12 months of Tx: CCyRAfter 2 month, WBC 25,000/ul & 15 % basophils, BM: Blast 16%.What step would you take next?
Continue imatinib at 400 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to a 2nd generation TKIRecommend immediate alloHSCT
Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response
Time Failure Suboptimal Response Warnings
Dx
•High risk •Del9q+ •Additional ch’somal abNLs in Ph+ cellsPh cells
3 m No HR < CHR
6 m No CHR or CyR < PCyR
12 m < PCyR PCyR < < CCyR Any MR < MMRy y y y
18 m < CCyR < MMR
Any•Loss of CHR •Loss of CCyR
•Additional ch’somal abNLs in Ph+ cells •Increase in BCR-Any
time•Loss of CCyR •Mutation with high insensitivity to Glivec
abNLs in Ph+ cells •Loss of MMR •Mutation with low insensitivity to Glivec
ABL level •Other ch’somal abNLs in Ph-cells
Baccarani M et al. Blood 2006;108:1809.
CASE 168/F, CML-CP in Jan 2004.Frontline Tx: Imatinib 400 mg/d. At 12 months of Tx: CCyRAfter 2 month, WBC 25,000/ul & 15 % basophils, BM: Blast 16%.What step would you take next?
Continue imatinib at 400 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to a 2nd generation TKIRecommend immediate alloHSCT
Pt shows imatinib failure after optimal responsethan
CASE 244/F, CML-CP, with sibling HLA matched donorFrontline Tx: Imatinib 400 mg/d. Grade 2 fluid retentionsPh(+) metaphases in BM: 30% at 6 months 50% at 12 monthsImatinib plasma level: adequate & No mutationsWhat step would you take next?
Increase the dose of imatinib to 800 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to nilotinib 400 mg twice dailySwitch therapy to dasatinib 100 mg dailySwitch therapy to dasatinib 100 mg dailyRecommend immediate alloHSCT
CASE 244/F, CML-CP, with sibling HLA matched donorFrontline Tx: Imatinib 400 mg/d. Grade 2 fluid retentionsPh(+) metaphases in BM: 30% at 6 months 50% at 12 monthsImatinib plasma level: adequate & No mutationsWhat step would you take next?
Increase the dose of imatinib to 800 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to nilotinib 400 mg twice dailySwitch therapy to dasatinib 100 mg dailySwitch therapy to dasatinib 100 mg dailyRecommend immediate alloHSCT
Pt shows imatinib failure after optimal responsethan or
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